When doctors won't tell . . .
Of all the online nutritional information, nutritional facts, medical and
dietary sites there are to choose from, in an article entitled "How
to ease the pain" The Sunday Times magazine,
Culture, published a list of just five websites it
considered reliable and informative.This site was one of that five.

CONDITIONS
AND DISEASES PREVENTED AND HELPED BY A LOW-CARB, HIGH-FAT DIET

Immune System Effects of Phytoestrogens

Reports in the scientific literature
of the potential effects of soy on immune system function have
been numerous over the last five years. In particular
the ability of the soy phytoestrogen genistein to inhibit tyrosine
kinases is well documented. The slant of much of the research
into this aspect of soy has been toward the possible role of
genistein in fighting cancer, but Soy Online Service believes
the potential for soy cause immune system disorders has been
overlooked.

Soy Online Service often receives
reports of the association of another auto-immune disease with
soy consumption, both in adults and in children who had been
fed soy formulas as infants. That disease is alopecia. Read
the experience of such a victim here
http://members.aol.com/greentek/hairloss.html.

References

Excessive soy consumption has
been linked to migraine pain. Read
more about this here.

An article published in Scientific
American (2002) suggests soy infant formula may impair the developing
immune system.
Read More Here

The literature is replete with
numerous studies showing deleterious effects on multiple organ
systems - including the immune system. For example this
letter from the American
Journal of Clinical Nutrition.

Early exposure to genistein exerts
long-lasting effects on the endocrine and immune systems
in rats.

Klein SL, Wisniewski AB, Marson AL, Glass
GE, Gearhart JP.

Mol Med 2002 Nov;8(11):742-9

Discussion: These data illustrate
that exposure to genistein during pregnancy and lactation exerts
long-lasting effects on the endocrine and immune systems in
adulthood. Whether exposure to phytoestrogens during early development
affects responses to infectious or autoimmune diseases, as well
as cancers, later in life requires investigation.

Use of soy-based infant formulas
and soy/isoflavone supplements has aroused concern because of
potential estrogenic effects of the soy isoflavones genistein
and daidzein.

...genistein produced suppression
of humoral immunity.

Genistein injected at 8 mg/kg
per day produced serum genistein levels comparable to those
reported in soy-fed human infants, and this dose caused significant
thymic and immune changes in mice.

Critically, dietary genistein
at concentrations that produced serum genistein levels substantially
less than those in soy-fed infants produced marked thymic atrophy.
These results raise the possibility that serum genistein concentrations
found in soy-fed infants may be capable of producing thymic
and immune abnormalities, as suggested by previous reports of
immune impairments in soy-fed human infants.

We have evaluated the hypothesis of a
protective effect of human milk on the development of insulin
dependent diabetes mellitus (IDDM). We studied the feeding
histories of 95 diabetic children and compared them with
controls consisting of their non-diabetic siblings and a
pair matched group of nondiabetic peers of the same age,
sex, geographical location, and social background. The incidence
of breast feeding in diabetic children was 18%. This was
similar to the control group. The duration of breast feedings
was also similar among all three groups. There was no difference
in the age of introduction of solid food between diabetic
and nondiabetic children. Twice as many diabetic children,
however, received soy containing formula in infancy as compared
to control children. The mean age of onset of IDDM was not
related to the type of feeding during infancy. The incidence
of positive thyroid antibodies was two and one half times
higher in formula-fed diabetic children than in breast-fed
ones. In our studies we were unable to document any relationship
between the history of breast feeding and subsequent development
of IDDM in children.

It has been suggested that feeding practices
in infancy may affect the development of various autoimmune
diseases later in life. Since thyroid alterations are among
the most frequently encountered autoimmune conditions in
children, we studied whether breast and soy-containing formula
feedings in early life were associated with the subsequent
development of autoimmune thyroid disease. A detailed history
of feeding practices was obtained in 59 children with autoimmune
thyroid disease, their 76 healthy siblings, and 54 healthy
nonrelated control children. There was no difference in
the frequency and duration of breast feeding in early life
among the three groups of children. However, the frequency
of feedings with soy-based milk formulas in early life was
significantly higher in children with autoimmune thyroid
disease (prevalence 31%) as compared with their siblings
(prevalence 12%; chi 2 = 7.22 with continuity factor; p
less than 0.01), and healthy nonrelated control children
(prevalence 13%, chi 2 = 5.03 with continuity factor; p
less than 0.02). Therefore, this retrospective analysis
documents the association of soy formula feedings in infancy
and autoimmune thyroid disease.

Errors in chromosome orientation in mitosis
and meiosis are inevitable, but normally they are quickly
corrected. We find that such errors usually are not corrected
in cells treated with protein kinase inhibitors. Highly
inaccurate chromosome distribution is the result. When grasshopper
spermatocytes were treated with the kinase inhibitor 6-dimethylaminopurine
(DMAP), 84% of maloriented chromosomes failed to reorient;
in anaphase, both partner chromosomes were distributed to
the same daughter cell. These chromosomes were observed
for a total of over 60 h, and not a single reorientation
was seen. In contrast, in untreated cells, maloriented chromosomes
invariably reoriented, and quickly: in 10 min, on average.
A second protein kinase inhibitor, genistein, had exactly
the same effect as DMAP. DMAP affected PtK1 cells in mitosis
as it did spermatocytes in meiosis: improper chromosome
orientations persisted, leading to frequent errors in distribution.
We micromanipulated chromosomes in spermatocytes treated
with DMAP to learn why maloriented chromosomes often fail
to reorient. Reorientation requires the loss of improper
microtubule attachments and the acquisition of new, properly
directed kinetochore microtubules. Micromanipulation experiments
disclose that neither the loss of old nor the acquisition
of new microtubules is sufficiently affected by DMAP to
account for the indefinite persistence of malorientations.
Drug treatment causes a novel form of chromosome movement
in which one kinetochore moves toward another kinetochore.
Two kinetochores in the same chromosome or in different
chromosomes can participate, producing varied, dance-like
movements executed by one or two chromosomes. These kinetochore-kinetochore
interactions evidently are at the expense of kinetochore-spindle
interactions. We propose that malorientations persist in
treated cells because the kinetochores have numerous, short
microtubules with a free end that can be captured by a second
kinetochore. Kinetochores capture each other's kinetochore
microtubules, leaving too few sites available for the efficient
capture of spindle microtubules. Since the efficient capture
of spindle microtubules is essential for the correction
of errors, failure of capture allows malorientations to
persist. Whether the effects of DMAP actually are due to
protein kinase inhibition remains to be seen. In any case,
DMAP reveals interactions of one kinetochore with another,
which, though ordinarily suppressed, have implications for
normal mitosis.

Selected flavonoids were tested for their
ability to inhibit the catalytic activity of DNA topoisomerase
(topo) I and II. Myricetin, quercetin, fisetin, and morin
were found to inhibit both enzymes, while phloretin, kaempferol,
and 4',6,7-trihydroxyisoflavone inhibited topo II without
inhibiting topo I. Flavonoids demonstrating potent topo
I and II inhibition required hydroxyl group substitution
at the C-3, C-7, C-3', and C-4' positions and also required
a keto group at C-4. Additional B-ring hydroxylation enhanced
flavonoid topo I inhibitory action. A C-2, C-3 double bond
was also required, but when the A ring is opened, the requirement
for the double bond was eliminated. Genistein has been previously
reported to stabilize the covalent topo II-DNA cleavage
complex and thus function as a topo II poison. All flavonoids
were tested for their ability to stabilize the cleavage
complex between topo I or topo II and DNA. None of the agents
stabilized the topo I-DNA cleavage complex, but prunetin,
quercetin, kaempferol, and apigenin stabilized the topo
II DNA-complex. Competition experiments have shown that
genistein-induced topo II-mediated DNA cleavage can be inhibited
by myricetin, suggesting that both types of inhibitors (antagonists
and poisons) interact with the same functional domain of
their target enzyme. These results are of use for the selection
of flavonoids that can inhibit specific topoisomerases at
specific stages of the topoisomerization reaction.

Genistein as an inducer of tumor
cell differentiation: possible mechanisms of action.

Constantinou A, Huberman E

Proc Soc Exp Biol Med 1995 Jan 208:1
109-15

Abstract

Decreased activity of either topoisomerases
or tyrosine kinases has been implicated in the differentiation
of a number of cell types. It is therefore conceivable that
genistein, because of its reported ability to inhibit these
activities in vitro, may be an inducer of cellular differentiation.
We investigated this possibility in human promyelocytic
HL-60 and erythroid K-562 leukemia cells and in human SK-MEL-131
melanoma cells. Our results indicated that genistein, in
a dose-dependent manner, inhibited cell multiplication and
induced cell differentiation. The maturing HL-60 cells acquired
granulocytic and monocytic markers. The differentiating
K-562 cells stained positively with benzidine, which indicates
the production of hemoglobin, an erythroid marker. Following
genistein treatment, maturing SK-MEL-131 melanoma cells
formed dendrite-like structures and exhibited increased
tyrosinase activity and melanin content. Experiments were
designed to identify the molecular mechanism of genistein's
action. Data from our laboratory suggest that this isoflavone
triggers the pathway that leads to cellular differentiation
by stabilizing protein-linked DNA strand breakage. Other
possible mechanisms reported in the literature are discussed.

The toxicity of genistein, an inhibitor
of tyrosine kinases and topoisomerase-II, on human thymocytes
was investigated. Genistein induced marked chromatin fragmentation
indicative of apoptosis in human thymocyte cultures. Genistein-induced
thymocyte apoptosis is unlikely due to an inhibition of
basal tyrosine kinase activity, since another tyrosine kinase
inhibitor, herbimycin A, does not induce thymocyte apoptosis,
whereas other topoisomerase-II inhibitors do. The thymocyte
subpopulation most sensitive to genistein-induced apoptosis
exhibited a CD3-CD4+CD8+ phenotype. This subpopulation of
thymocytes is also sensitive to glucocorticoid-induced apoptosis;
however, differences between genistein- and glucocorticoid-induced
apoptosis were noted. In particular, unlike glucocorticoid-induced
apoptosis, genistein-induced apoptosis does not involve
changes in [Ca2+]i and cannot be blocked by activation of
protein kinase C.

The phytoestrogen, genistein, is a naturally
occurring isoflavone found in soy products. On a biochemical
basis, genistein is a competitive inhibitor of tyrosine
kinases and the DNA synthesis-related enzyme, topoisomerase-II
(topo-II). Exposure of mammalian cells to genistein results
in DNA damage that is similar to that induced by the topo-II
inhibitor and chromosomal mutagen, m-amsa. In order to determine
the potential genotoxicity of genistein, human lymphoblastoid
cells which differ in the functional status of the tumor
suppressor gene, p53, were exposed to genistein and the
induction of micronuclei quantified by
microscopic analysis. In addition, the mutant fraction at
the thymidine kinase (tk) locus (both the normal-growth
and slow-growth phenotypes) was determined by resistance
to trifluorothymidine (TFT) and at the hypoxanthine phosphoribosyl
transferase (hprt) locus by resistance to 6-thioguanine
(6-TG). Flow cytometric analysis of the percentage of viable,
apoptotic and degenerating cells was utilized to determine
the rate and kinetics of cell death after genistein exposure.
The detection of micronuclei in both cell lines indicated
that genistein-induced damage had occurred in both AHH-1
tk+/- and L3. Linear regression analysis detected a significant
increase in the number of 6-TG-resistant clones in both
AHH-1 tk+/- (p53+/-) and L3 (p53+/+). A comparison of slopes
revealed no difference between the lines. In contrast, a
significant, concentration-dependent increase in the number
of TFT-resistant clones with the slow-growth phenotype was
detected in AHH-1 tk+/- (mutant p53), but not in L3 (wild-type
p53). Cell death occurred primarily by apoptosis in both
cell lines; however, a concentration-dependent decrease
in the percentage of viable cells was detected immediately
after exposure in L3, but not until 32 h after exposure
in AHH-1 tk+/-. A comparison of the slopes of the concentration-response
curves for the percentage of viable cells revealed no difference
between the cell lines in the effect of genistein on cell
viability. Our results may be interpreted that genistein
is a chromosomal mutagen and that p53 functional status
affects the recovery of chromosomal mutants, possibly by
signalling cells into the apoptosis pathways.

Induction of mouse thymocyte
apoptosis by inhibitors of tyrosine kinases is associated
with dephosphorylation of nuclear proteins.

Azuma Y, Onishi Y, Sato Y, Kizaki H

Cell Immunol 1993 Nov 152:1 271-8

Abstract

Incubation of mouse thymocytes with the
protein tyrosine kinase inhibitors herbimycin A and methyl-2,5-dihydroxycinnamate
induced a decreased and altered profile of nuclear phosphotyrosine
proteins in parallel with an increase in internucleosomal
DNA fragmentation and cell death dose-dependently. No change
in the profile of cytoplasmic phosphotyrosine proteins was
observed. DNA fragmentation was dependent on the synthesis
of RNA and protein, suggesting that the inhibition of tyrosine
phosphorylation of the nuclear proteins induces apoptosis.
DNA fragmentation was enhanced by simultaneous incubation
with
phorbol esters capable of activating protein kinase C. Genistein,
another inhibitor of protein tyrosine kinase, induced DNA
fragmentation more rapidly than herbimycin A, but there
was no predominant alteration of phosphotyrosine proteins
in early incubation, suggesting that genistein may induce
apoptosis by a mechanism other than direct inhibition of
protein tyrosinekinase activity.

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